{
  "abstract": "Background IGSF9, immunoglobulin superfamily member 9, has been reported to inhibit T cell proliferation and activation, thereby promoting tumor immune escape. Tumor-associated macrophages (TAMs), the most abundant tumor-infiltrating immune cells, play a crucial role in forming the immunosuppressive tumor microenvironment. We find that IGSF9 strongly binds to TAMs, however, how it affects TAMs function remains unreported.Methods The spatial transcriptomics dataset (GSE189487) was analyzed to clarify the relationship among IGSF9, senescent TAMs, and T cells. RNA-seq revealed differentially expressed genes. Flow cytometry was employed to assess the binding of IGSF9-ECD proteins to macrophages. Macrophage-educated by IGSF9 were co-cultured with T cells, and the phagocytosis was observed. Membrane-system yeast two-hybrid screening, GST pull-down, and co-IP were used to identify the binding partner of IGSF9. Cellular senescence markers and the senescence-associated secretory phenotype (SASP) were assessed by flow cytometry and immunofluorescence. LL/2-control or LL/2- Igsf9 cells were injected into C57BL/6, NSG, and monocytes-depleted C57BL/6 mice. Similarly, MC38-OVA-control or MC38-OVA-Igsf9 cells were inoculated into OT-II mice. Finally, anti-IGSF9 and its LALA-PG-mutant variant were administered to C57BL/6 mice to monitor tumor growth and SASP expression.Results The spatial transcriptomics dataset (GSE189487) revealed that the level of IGSF9 in tumor cells was positively correlated with the senescence of TAMs, and RNA-seq revealed the differentially expressed genes which were related to senescence. Macrophage educated by IGSF9 exhibited distinct senescence phenotypes and immunosuppressive features, and IGSF9 bound to TMUB1 to activate the IL-6/STAT3 signal pathway to trigger the above phenotype. In vivo data showed that IGSF9 could induce TAM senescence, leading to inhibition of T cell activity and formation of an immunosuppressive microenvironment, then promoting tumor immune escape. Treatment with anti-IGSF9, including the LALAPG-mutant variant that reduces antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis, mitigated TAM senescence and immunosuppression, activated T cells, and suppressed tumor growth.Conclusions TMUB1 as a binding protein of IGSF9 is first discovered, and TAMs educated by IGSF9 exhibit senescent and suppressive phenotype to orchestrate an inhibitory tumor microenvironment, which can be reversed by anti-IGSF9 to suppress tumor progression.",
  "authors": [
    {
      "affiliations": [
        "Department of Biochemistry and Molecular Biology, School of Life Sciences, Shandong Agricultural University, Tai'an, Shandong, China",
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Jiasheng Zhang"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Xianhui Meng"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Xinyu Zhao"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Huiwen Luan"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Fangmin Li"
    },
    {
      "affiliations": [
        "Department of Pathology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong, China"
      ],
      "name": "Ting Wang"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Yuxiao Sun"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou University Medical College, Shantou, Guangdong, China"
      ],
      "name": "Guantong Liu"
    },
    {
      "affiliations": [
        "Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, Shandong, China"
      ],
      "name": "Yingxin Pang"
    },
    {
      "affiliations": [
        "Taishan Vocational College of Nursing, Tai’an, Shandong, China"
      ],
      "name": "Aihui Xu"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Hongying Wang"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Chunling Li"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Lijun Hui"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Fang Li"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Shuping Wei"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Hong Yu"
    },
    {
      "affiliations": [
        "Department of thoracic surgery, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, Shandong, China"
      ],
      "name": "Yaopeng Wang"
    },
    {
      "affiliations": [
        "Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medicine and Health Key Lab of Respiratory Infection and Tumor Immunity, Department of Biochemistry and Molecular Biology, Shandong Tumour Immunotherapy Research Innovation Team, Binzhou Medical University, Yantai, Shandong, China"
      ],
      "name": "Zunling Li"
    }
  ],
  "title": "Tumor-associated macrophages educated by IGSF9 exhibit a senescence-associated secretory phenotype to promote tumor immune escape",
  "uid": "aca46609-f316-5cad-b6d5-6ee3be0d81ca"
}